Adhesion is crucial in the regulation of immune response and epithelial cell differentiation, morphogenesis, and function. Three classes of proteins are identified to be important in adhesion: cadherins, selectins, and immunoglobulins. To detect antigenic exposure in tissues, extravasation by lymphocytes requires successive formation and breaking of cell-cell contacts between leukocytes in the blood and endothelial cells. Exposure to pro-inflammatory mediators, such as cytokines, lipopolysaccaride endotoxin and tumor necrosis factor, increases the adhesion of lymphocytes to endothelial cells, and consequently, the expression levels of intracellular and vascular adhesion proteins (Pinola, M. et al. (1992) Scand. J. Immunol. 36:671-679). Loss of expression of cadherins and related molecules is associated with loss of the control of epithelial cell proliferation (Field, J. K. (1992) Eur. J. Cancer (B) 28B: 67-76).
Adhesion is achieved through tight junctions, adherens junctions, spot desmosomes, hemidesmosomes, or gap junctions. Particularly, adherens junctions participate in cell-cell interactions through their association with a protein tyrosine kinase (PTK)-mediated signaling pathway. Two such kinases, c-Yes and c-Src, are highly enriched in the adherens junctions of hepatocytes, kidney epithelial cells and keratinocytes (Tsukita, S. et al. (1991) J. Cell Biol. 113:876-879). Expression of the oncogenic v-Src in epithelial cells results in high levels of tyrosine phosphorylation, breakdown of adherens junctions and loss of cell-cell adhesion (Volberg, T. et al. (1991) Cell Regul. 2:105-120).
PTKs regulate a variety of signal transduction pathways crucial for cell differentiation and function. The regulation is achieved through a cascade of protein-protein interactions involving PTKs and proteins containing PTK-binding elements. Src-homology-2 (SH2), Src-homology-3 (SH3), and pleckstrin homology (PH) domains are all PTK-binding elements which in turn bind short phosphotyrosine-containing peptides, proline-rich domains (PRDs), and phospholipids, respectively.
A SH3-binding PRD generally contains 7 to 10 amino acid residues and a consensus sequence of X-P-X-X-P, where X is usually an aliphatic residue. Upon SH3 binding, the PRD forms a pseudo-symmetrical class I or class II left-handed poly-proline helix. Specificity is conferred by the interactions between non-proline residues in the PRD and two variable SH3 loops flanking the main hydrophobic binding surface (Pawson, T. (1995) Nature 373:573-580).
Recently, a mouse T cell surface glycoprotein CD6 was reported to contain two SH3-binding PRDs, nine casein kinase II phosphorylation site motifs, and a serine/threonine-rich motif which is repeated three times (Robinson, W. H. et al. (1995) J. Immunol. 155:4739-4748). A mouse acidic casein family protein induced by pregnancy was found to be proline-rich (GI 899433). Other examples of PRDs involving PTK signaling include kinases Btk and Itk (Yang, W. et al. (1995) J. Biol. Chem. 270: 20832-20840), the human potassium channel protein Kv1.5 (Holmes, T. C. et al. (1996) Science 274:2089-2091), and the N-methyl D-aspartate (NMDA) receptor complex (Kumar, K. N. et al. (1991) Nature 354:70-73).
The discovery of proteins related to a human proline-rich acidic protein and the oligonucleotides encoding them satisfies a need in the art by providing new compositions which are useful in diagnosing, preventing, and treating inflammation and disorders associated with abnormal cell proliferation.